Clinical Phenotype Associated With the Arg141His Mutation in the X-linked Retinoschisis Gene

X-linked retinoschisis (XLRS) is a rare hereditary disorder characterized by bilateral stellate maculopathy and peripheral retinoschisis. The schisis cavities are usually first noted in the inferotemporal quadrant and often progress to involve the entire peripheral retina. This process often commences within the first year of life and is associated with a wide range of phenotypic expression.¹ Histopathologic studies have demonstrated a splitting of the retina at the nerve fiber layer.² A gene responsible for XLRS, XLRS-1, which maps to Xp22.2, has been cloned and sequenced. The predicted protein sequence contains a highly conserved motif implicated in cell-cell interaction and, thus, may be active in cell adhesion processes.³ We report the clinical and electrodiagnostic phenotype associated with a missense point mutation within the fifth exon of this gene that replaces the normal arginine residue with a histidine residue at codon 141 in a family of Hispanic origin.

The proband was initially seen at age 1 year 5 months, after his parents noted the evolution of an alternating esotropia. Family review disclosed 2 brothers who had decreased central visual acuity, in one of whom it was associated with esotropia (Table 1). Examination of the proband and his siblings revealed bilateral, bullous schisis cavities, more prominent in the inferior quadrants, and foveal changes consistent with a diagnosis of XLRS (Figure 1). No retinal breaks or dialyses were noted. Funduscopic examination results of the proband's mother and sister were normal.

Abbreviated standardized electroretinograms were recorded from each participant in accordance with international standards for pediatric patients⁴ (Figure 2). The full-field mesoscopic electroretinograms described here were elicited after 20 minutes of dark adaptation using a 10-microsecond xenon strobe (model PS-22; Grass Instruments, Quincy, Mass) at an intensity of 2.4 candelas/m² and a rate of 0.3 Hz (4 responses averaged). All electroretinograms were recorded with Burian-Allen contact lens electrodes (Hansen Ophthalmic Development Laboratories, Iowa City, Iowa) using the Neuroscan electrodiagnostic system v3.0 (Neurosoft Inc, Herndon, Va). The A wave was of normal amplitude for all participants; however, the B waves were reduced in each of the 3 male siblings under mesoscopic conditions. Electrodiagnostic testing of the proband's mother revealed a B wave of reduced amplitude but within normal limits. Similar testing of the proband's sister was normal. The B/A ratio, which shows the relative relationship of B-wave to A-wave amplitude and should be between 1.5 and 1.7 for most normal individuals,⁵ was severely abnormal in the 3 male siblings (0.77, 0.58, and 0.66), borderline normal in the mother (1.4), and clearly normal in the sister (2.1).

A peripheral blood sample was obtained from each family member and genomic DNA was isolated by proteinase-K incubation followed by phenol/chloroform extraction. Oligonucleotide polymerase chain reaction primers, able to amplify each exon of the XLRS-1 gene, were synthesized (sequences available on request). Fluorescent-labeled dideoxynucleotides were used in direct sequencing of polymerase chain reaction products to study the XLRS-1 gene for each family member. Each exon was aligned to wildtype sequence available on the Entrez nucleotide database (Accession No. AF018958). A G to A transition resulted in the substitution of a histidine residue for an arginine residue at codon 141 of exon 5 for each affected male sibling (Figure 2). The proband's mother and sister were noted to be heterozygous for this mutation. No other mutation or polymorphism was identified in any other exon. This mutation was not seen in 32 control chromosomes.

The Retinoschisis Consortium has described a wide spectrum of mutations in the XLRS-1 gene in patients from a variety of ethnic backgrounds.⁶ The mutation we report has been previously identified by the Retinoschisis Consortium⁶ and is clearly associated with early clinical, visual, and electrophysiologic changes, as the affected proband had central and peripheral retinal changes, as well as strabismus and electroretinographic changes, by the age of 17 months. In addition, DNA sequence analysis permitted the identification of the proband's sister as a carrier prior to the development of electoretinographic changes. The ability to determine carrier status by molecular techniques is important as many female carriers of XLRS achieve childbearing age prior to the detection of electroretinographic changes. Useful family counseling is enhanced by the development of rapid, reliable genotype assays.

Corresponding author: J. Timothy Stout, MD, PhD, 4650 Sunset Blvd, Mail Stop 88, Los Angeles, CA 90027 (e-mail: jtstout@rocketmail.com).

We have no proprietary interest in any material relating to this research project.

Corresponding author: Mark J. Kupersmith, MD, INN at Beth Israel North, 170 East End Ave, New York, NY 10128 (e-mail: mkuper@bethisraelny.org).

Corresponding author: Craig G. Burkhart, MSPH, MD, Department of Medicine, Medical College of Ohio at Toledo, 5600 Monroe St, Suite 106B, Sylvania, OH 43560.